Synthesis of Indoles from 2-Vinylanilines with PIFA or TFA and Quinones

Article abstract of DOI:10.1055/s-0036-1588122

The cyclizations involved in the synthesis of different indoles from 2-vinylanilines with PIFA {[bis(trifluoroacetoxy)iodo]benzene} and quinones have been developed under mild conditions. Various substituents on 2-vinylanilines induced good compatibility and gave the desired products in moderate to good yields.

Full text of DOI:10.1055/s-0036-1588122

SYNLETT
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Imprimatur:
© Georg Thieme Verlag Stuttgart · New York
Date, Signature
st-2016-w0679-l.fm
2016, 27, A–E
letter
A
12/13/16
M. Wu, R. Yan
Letter
Synlett
Synthesis of Indoles from 2-Vinylanilines with PIFA or TFA and
Quinones
Mingzhong Wu
R2
R4
Rulong Yan*
R2
R4
R1
R1
quinones, TFA
DMA, 70 °C, Ar
N
State Key Laboratory of Applied Organic Chemistry, Key
laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, Department of Chemistry,
Lanzhou University, Lanzhou 730000, Gansu, P. R. of China
yanrl@lzu.edu.cn
PIFA
R2
R4
R1
1,4-dioxane, rt
N
R3
NH
R3
OH
different oxidants for different indoles
R1 = H, alkyl, F, Cl, Br
R1 = H, alkyl, F, Cl, Br
2 = H, (aetero)aryl
R3 = H, Me
4 = Me, Ph
11 examples, up to 78% yield
R
2 = H, (hetero)aryl
R
R3 = H
R4 = Me, Ph
R
16 examples, up to 85% yield
Received: 10.10.2016
Accepted after revision: 25.11.2016
Published online:
As a starting point for the development of our direct
amination, we initially used 2-(1-phenylvinyl)aniline (1a)
as the test substrate for optimizing the reaction conditions
(Table 1). Originally, iodosobenzene (PhIO) was employed
as the oxidant.
DOI: 10.1055/s-0036-1588122; Art ID: st-2016-w0679-l
Abstract The cyclizations involved in the synthesis of different indoles
from 2-vinylanilines with PIFA {[bis(trifluoroacetoxy)iodo]benzene} and
quinones have been developed under mild conditions. Various substitu-
ents on 2-vinylanilines induced good compatibility and gave the desired
products in moderate to good yields.
Table 1 Optimization of the Reaction Conditionsa
Ph
Ph
Keywords 2-vinylanilines, PIFA, quinones, oxidant, indoles
conditions
N
H
NH2
Indoles, as one of the most important and valuable het-
erocycles, are prevalent in the activation of biological activ-
ities, medical chemistry, and material sciences.1 In addition,
the indole moiety is also a key intermediate for many or-
ganic synthesis.2 In view of these benefits, a number of dif-
ferent methods for the synthesis of indole derivatives have
been developed in the past several years.3 The predominant
strategy relies on the transition-metal-catalyzed coupling
reactions to build new C–N bonds for the rapid access to
useful indole derivatives.4 When this approach was report-
ed by the research group of Hegedus, the Pd(II)-catalyzed
C–H amination of 2-vinylanilines has been considered as an
effective pathway toward the production of the indole skel-
eton (Scheme 1, a).5 Zheng and co-workers reported a new
type of reactivity of nitrogen-centered radical cations for
the synthesis of indoles (Scheme 1, b).6 Recently, Youn and
co-workers, showed an operationally effective and straight-
forward metal-free C–H amination able to afford a broad
range of substituted indoles.7 Nevertheless, the search for
sustainable and more efficient methods for the preparation
of indoles is of constant interest.8 In this paper, we commu-
nicate metal-free methods for the synthesis of different in-
doles from 2-vinylanilines with different oxidants PIFA and
quinones.
2a
1a
Entry
Oxidant
Solvent
Yield (%)
1
2
PhIOb
PhIO
DMP
I2 + K2S2O8
PIDA
PIDA
DDQ
PIFA
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
40
43
3
12
–
4
5
58
60
51
62
42
45
62
74
50
78
6c
7c
8
9
PIFA
10
11
12
13
14
PIFA
EtOH
DCE
PIFA
PIFA
THF
PIFA
toluene
PIFA
1,4-dioxane
a Reaction conditions: 1a (0.3 mmol), oxidant (0.36 mmol), solvent (1 mlL),
1.5 h, r.t.
b The reaction was carried out at 70 °C for 24 h.
c Amount of AcOH used was 20 mol%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
M. Wu, R. Yan
Letter
Synlett
Hegedus's work:
R1
R1
R2
Pd(II), oxidant
R2
(a)
(b)
NHR
N
R
Zheng' work:
R1
Ru(II), hv
R1
NH
Ar
N
Ar
O
O
This work:
R2
R2
R4
H
R4
R1
PIFA
R2
N
R4
R1
R1
N
R3
NH
R3
OH
(R3 = H)
Scheme 1 Typical routes and our strategy for the synthesis of substituted indoles
Using PhIO (1.2 equiv) in methyl cyanide (MeCN) and
leaving the reaction mixture at 70 °C, produced the desired
product in 40% yield, although, even after 24 hours, the re-
action was not completed (Table 1, entry 1). The tempera-
ture was optimized and the results indicated that the best
yield was obtained at room temperature to afford the in-
dole in 43% yield (Table 1, entry 2). Then, various oxidants
were evaluated and the results revealed that PIFA was the
most effective oxidant by producing the compound 2a in
62% yield (Table 1, entries 1−8). The screening of different
solvents, N,N-dimethylformamide (DMF), ethanol, 1,2-di-
chloroethane (DCE), tetrahydrofuran (THF), toluene and
1,4-dioxane, showed that 1,4-dioxane provided the best
yield (Table 1, entries 9−14). We further determined that ei-
ther reducing or increasing the amount of PIFA led to lower
yields of 2a. The optimized conditions were then estab-
lished and are shown in Table 1 (entry 14).
Under the optimized conditions, a wide range of 2-vi-
nylanilines were examined and the results are summarized
in Table 2.9 The electron-withdrawing and electron-donat-
ing groups on the aromatic ring and nitrogen atom of 2-vi-
nylanilines were compatible and gave the desired products
in moderate to good yields. Alkenes with different R2 and R3
groups were also employed to generate the corresponding
substituted indoles in 73% and 68% yields, respectively (Ta-
ble 2, entries 6 and 7). Subsequently, diverse substituents
on the aromatic and vinyl moieties of 2-vinylanilines were
also investigated, which led to the desired products 2h and
2i in 63% and 57% yields, respectively (Table 2, entries 8 and
9). Unfortunately, the substrates of α,β-disubstituted and
α,α,β-trisubstituted were not tolerated in this transforma-
tion and the desired products 2j and 2k were not isolated.
Table 2 Synthesis of Indole Derivatives with 2-Vinylanilines and PIFA
R4
R2
R1
R1
R2
PIFA (1.2 equiv)
R4
1,4-dioxane, rt, 1.5 h
N
R3
NH
R3
2
1
Entry
R1
R2
R3
R4
Yield (%)a
1
2
H
Ph
H
H
H
H
H
H
78 (2a)
64 (2b)
63 (2c)
71 (2d)
56 (2e)
73 (2f)
68 (2g)
63 (2h)
57 (2i)
– (2j)
Me
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
Ph
3
i-Pr
4
t-Bu
F
5
6
H
4-MeC6H4
Ph
H
7
H
Me
H
8
Br
Cl
H
4-FC6H4
4-ClC6H4
H
9
H
10
11
H
H
Ph
H
Me
trace (2k)
a Yields of isolated products.
In the course of optimizing the experimental condi-
tions, different indoles were detected when the oxidant
benzoquinone was used. The product 4-(3-phenyl-1H-in-
dol-1-yl)phenol (3a) was produced with 2-(1-phenylvi-
nyl)aniline (1a) and benzoquinone in the presence of acetic
acid (AcOH) as catalyst. Subsequently, we extensively
screened acids, solvents, and other factors under argon. The
results are summarized in Table S1 (Supporting Informa-
tion). The highest yield of 3a was achieved when the reac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
M. Wu, R. Yan
Letter
Synlett
tion was carried out with 1a and benzoquinone (1.2 equiv),
trifluoroacetic acid (TFA; 20 mol%) in N,N-dimethylacet-
amide (DMA) at 70 °C under argon (Table S1, entry 13).
Next, we investigated the reaction scopes under the op-
timized conditions to synthesize indoles and the results are
listed in Scheme 2.10 As shown in Scheme 2, the anilines
carrying an ortho-terminal alkene (R2 = Me, Ph) produced
the N-arylindoles 3a and 3b in moderate yields. Moreover,
the reaction was not significantly affected by the nature of
the groups of the aromatic ring of 2-vinylanilines. The or-
tho, meta, and para positions of the substituents of the sub-
strates did not have a considerable effect on the efficiency
of the reaction. For example, the 2-vinylanilines presenting
methyl group could afford the desired products 3c and 3d
in 69% and 85% yields, respectively. The reaction with naph-
thalene-1,4-dione was also satisfactory by producing 3m in
49% yield. The product N-arylindole 3n could also be ob-
tained in 58% yield. Particularly, 2-(1-phenylprop-1-en-1-
yl)aniline could react with benzoquinone to give 3p in 76%
yield. Nevertheless, the reaction was incompatible with 2-
styrylaniline, and failed to give the desired product 3o.
■■include discussion of Figure 1■■
Figure 1 X-ray crystal structure of N-arylindole 3e
On the basis of the results described above, a plausible
mechanism pathway accounting for the conversion of these
two pathways is proposed in Scheme 3. One of the routes
describes the formation of the iodo intermediate 4 from the
reaction of the substrate 1a with PIFA by releasing trifluoro-
acetic acid. Then an intramolecular electrophilic cyclization
occurs on 4, with the release of one molecule each of iodo-
benzene, and trifluoroacetate acid, which leads to the for-
mation of the 3-phenyl-1H-indole (2a). Similarly, the other
route involves the reaction of the substrate 1a with the pro-
tonated benzoquinone to produce the imine 5. Intramolec-
ular electrophilic addition of the imine 5 forms the inter-
mediate 6. Finally, the desired product 3a is generated by
the proton elimination.
In conclusion, we have developed a novel and metal-free
method to easily prepare different indoles from 2-vinylani-
lines with PIFA, or with TFA and quinones■■changes OK?
PIFA not used with quinones■■. In this study, various sub-
stituted groups of 2-vinylanilines reacted smoothly and
produced the desired indoles in moderate to good yields.
R2
R4
O
R4
R1
N
TFA (0.2 equiv)
DMA, 70 °C, Ar
R2
R1
NH
R3
O
OH
F
1
3
R2
R1
Br
N
R1
N
N
N
OH
Acknowledgment
OH
OH
OH
3a (R2 = Ph), 80%
3b (R2 = Me), 50%
3c (R1 = 7-Me), 69%
3d (R1 = 6-Me), 85%
3e (R1 = MeO), 64%
3f (R1 = Me), 69%
3g (R1 = i-Pr), 70%
3h (R1 = t-Bu), 75%
3i (R1 = F), 74%
3j (R1 = Cl), 58%
3k (R1 = Br), 69%
3l, 75%
This work was supported by the National Natural Science Foundation
of China (21672086, 21202067), the Gansu Province Science Founda-
tion for Youths (1606RJYA260) and the Fundamental Research Funds
for the Central Universities (lzujbky-2016-39).
Supporting Information
Ph
N
Ph
N
Ph
N
Ph
N
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588122.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
OH
References and Notes
OH
OH
OH
3p, 76%
(1) (a) Kochanowska, K. A. J.; Hamann, M. T. Chem. Rev. 2010, 110,
4489. (b) Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem.
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Choi, E. Molecules 2013, 18, 6620.
3m, 49%
3n, 58%
3o, trace
Scheme 2 Synthesis of indoles with 2-vinylanilines and quinones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
M. Wu, R. Yan
Letter
Synlett
L
L
Ph
I
Ph
Ph
L–
HL
– HL
– PhI
– L–
N
NH
I
L = OCOCF3
H
Ph
L
Ph
4
2a
Ph
N
NH2
Ph
Ph
1a
N
N
– H+
– H2O
+ H+
OH
OH
OH
O
5
6
3a
O
Scheme 3 Proposed catalytic cycle
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1416.
(9) General Procedure for the Synthesis of Substituted Indoles
from 2-Vinylanilines with Oxidant PIFA: The 2-(1-phenylvi-
nyl)aniline (1a; 0.2 mmol) and PIFA (2.4 mmol) were added
weighed into a 10-mL vial equipped with a magnetic stir bar.
1,4-dioxane (1 mL) was added, and this mixture was stirred
under air. After being stirred at r.t. for 1.5 h, the solvent was
evaporated in vacuum and the crude product was purified by
column chromatography, eluting with petroleum ether–EtOAc
(10:1) to afford the desired product 2a as a colorless solid (32
mg, 78% yield); mp 75–77 °C. 1H NMR (400 MHz, CDCl3): δ =
8.01 (br s, 1 H), 7.93–7.95 (d, J = 8.0 Hz, 1 H), 7.64–7.67 (m, 2 H),
7.41–7.45 (m, 2 H), 7.33–7.35 (d, J = 8.0 Hz, 1 H), 7.16–7.29 (m,
4 H). 13C NMR (100 MHz, CDCl3): δ = 136.72, 135.64, 128.87,
127.56, 126.07, 125.79, 122.48, 121.90, 120.41, 119.88, 118.32,
111.52. HRMS: m/z [M + H]+ calcd for C14H12N: 194.0964; found:
194.0960.
(10) General Procedure for the Synthesis of Indole Derivatives
from 2-Vinylanilines with Oxidant Quinones: The 2-(1-
phenylvinyl)aniline (1a; 0.2 mmol), benzoquinone (1.2 equiv)
and TFA (0.2 equiv) were added weighed into a 10-mL vial
equipped with a magnetic stir bar, and DMA (1 mL) was added,
this mixture was stirred under Ar. After being stirred at 70 °C
for 5 h, the reaction mixture was cooled to r.t. and then
extracted with EtOAc (3 × 15 mL). The combined organic phase
was dried over anhyd Na2SO4. The solvent was evaporated in
vacuum and the crude product was purified by column chro-
matography, eluting with petroleum ether–EtOAc (10:1) to
afford the desired product 3a as a light pink solid; yield: 34 mg
(80%); mp 82–84 °C. 1H NMR (400 MHz, CDCl3): δ = 7.98–8.00
(m, 1 H), 7.69–7.72 (m, 2 H), 7.42–7.48 (m, 4 H), 7.35–7.39 (m, 2
H), 7.21–7.32 (m, 3 H), 6.93–6.95 (d, J = 8 Hz, 2 H), 5.24 (br s, 1
H). 13C NMR (100 MHz, CDCl3): δ = 154.74, 135.59, 134.62,
132.26, 129.09, 127.82, 127.59, 127.18, 127.07, 126.51, 126.32,
122.95, 119.58, 118.22, 116.46, 111.96. HRMS: m/z [M + H]+
(6) Maity, S.; Zheng, N. Angew. Chem. Int. Ed. 2012, 51, 9562.
(7) Jang, Y. H.; Youn, S. W. Org. Lett. 2014, 16, 3720.
(8) (a) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764. (b) Lu, B.;
Luo, Y.; Liu, L.; Ye, L.; Wang, Y.; Zhang, L. Angew. Chem. Int. Ed.
2011, 123, 8508. (c) Lu, B.; Luo, Y.; Liu, L.; Ye, L.; Wang, Y.;
Zhang, L. Angew. Chem. Int. Ed. 2011, 50, 8358. (d) Bandini, M.;
Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48, 9608. (e) Bandini,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
M. Wu, R. Yan
Letter
Synlett
calcd for C20H16NO: 286.1227; found: 286.1225.
8.0 Hz, 2 H), 6.04–6.06 (m, 1 H), 2.98 (s, 3 H). 13C NMR (100
MHz, DMSO-d6): δ = 156.74, 155.05, 135.60, 132.11, 130.90,
129.43, 127.66, 127.28, 126.91, 126.23, 126.05, 117.07, 116.65,
112.84, 112.11, 101.71, 55.92. HRMS: m/z [M + H]+ calcd for
4-(5-Methoxy-3-phenyl-1H-indol-1-yl)phenol (3e): light pink
solid; yield: 25 mg (64%); mp 89–91 °C. 1H NMR (400 MHz,
DMSO-d6): δ = 8.94 (br s, 1 H), 6.96 (s, 1 H), 6.90–6.92 (d, J = 8.0
Hz, 2 H), 6.54–6.65 (m, 6 H), 6.42–6.46 (m, 1 H), 6.14–6.16 (d, J =
C
20H15NO: 285.1148; found: 285.1144. ■■HRMS not for3e?■■
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E